SUMMARY OF WORK: We have defined the main mammalian base excision repair (BER) pathways in vitro using purified enzymes and cell extracts, and we have cloned the human and mouse genes for many of the enzymes, expressed the corresponding recombinant proteins in E. coli and insect cells, and prepared cell lines with genetic alterations in each gene. Transgenic mouse models are studied to understand the cellular and tissue requirements for each enzyme. This project includes studies of the cellular role of BER in overall cellular DNA repair, apoptosis, necrosis, check point control of the cell cycle, mutagenesis, chromosome stability, DNA lesion bypass, cell signaling, DNA replication control, and human and mouse carcinogenesis. The project also evaluates the effect of DNA synthesis inhibitors on cell cycle control and on the mechanism of cell death. Naturally occurring DNA synthesis inhibitors include oxidized nucleotides in the dNTP pool; these compounds have recently been implicated in DNA polymerase inhibition through a chain termination mechanism, producing toxic DNA strand breaks.This research on the effects of DNA synthesis chain terminators, such as oxidized dNTPs, informs the understanding of HIV-1 reverse transcriptase chain terminator drugs including the dideoxynucleosides.